The matrix metalloproteinases (MMP's) are a class of extracellular enzymes including collagenase, stromelysin, and gelatinase which are believed to be involved in the tissue destruction which accompanies a large number of disease states varying from arthritis to cancer.
Typical connective tissue cells are embedded within an extracellular matrix of high molecular weight proteins and glycoproteins. In healthy tissue, there is a continual and delicately-balanced series of processes which include cell division, matrix synthesis, and matrix degradation. In certain pathological conditions, an imbalance of these three processes can lead to improper tissue restructuring. For example, in arthritis, joint mobility can be lost when there is improper remodelling of load-bearing joint cartilage. In the case of cancer, lack of coordination of cell division and the two processes of matrix synthesis and degradation can lead to conversion of transformed cells to invasive phenotypes in which increased matrix turnover permits tumor cells to penetrate basement membranes surrounding capillaries leading to subsequent metastasis.
There has been heightened interest in discovering therapeutic agents which bind to and inhibit MMP's. The discovery of new therapeutic agents possessing this activity will lead to new drugs having a novel mechanism of action for combatting disease states involving tissue degenerative processes including, for example, rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal, epidermal or gastric ulceration, and tumor growth and metastasis or invasion.
Tumor Necrosis Factor .alpha. (TNF.alpha.) is a potent proinflammatory mediator which has been implicated in inflammatory conditions including arthritis, asthma, septic shock, non-insulin dependent diabetes mellitus and inflammatory bowel disease. TNF.alpha. is originally expressed as a membrane-bound protein of about 26 kD, which is proteolytically cleaved to release a soluble 17 kD fragment (TNF.alpha. processing) which combines with two other secreted TNF.alpha. molecules to form a circulating 51 kD homotrimer. Recently, several MMP inhibitors were found to inhibit TNF.alpha. processing (see Mohler, et al., Nature, 1994, 370, 218; Gearing, et al., Nature, 1994, 370, 555; and McGeehan, et al., Nature, 1994, 370, 558), leading to the hypothesis that TNF.alpha. processing is caused by an as yet uncharacterized metalloproteinase residing in the plasma membrane of cells producing TNF.alpha.. Inhibitors of this metalloproteinase would therefore be useful as therapeutics to treat disease states involving TNF.alpha. secretion.
Transforming growth factor alpha (TGF.alpha.) is a potent mitogen which ellicites its biological activity by binding to cell surface receptors, in particular epidermal growth factor (EGF) receptor. It is known to promote angiogenesis and to stimulate epithelial cell migration and therefore has been implicated in a number of malignant disorders such as breast cancer and ovarian carcinoma. TGF.alpha. is produced by proteolytic cleavage of a 160 amino acid membrane bound precursor. Several cleavage sites have been identified including Ala38-Val39, similar to the cleavage site of proTNF.alpha. (Ala-76-Val77). This common cleavage site suggests that inhibitors of TNF.alpha. processing may also block the cleavage of proTGF.alpha. and therefore would be therapeutically useful in diseases mediated by TGF.alpha..